Advanced age is a risk factor for several devastating neurodegenerative disorders, Alzheimer's disease being the most prevalent. How age predisposes one to these illnesses or how these diseases are initiated is unknown. Creutzfeldt-Jakob disease and Gerstmann-Straussler-Scheinker syndrome are human prion diseases which demonstrate age-associated neurodegeneration and promise to provide substantial insights into this problem as natural and experimental models of prion diseases in animals are available. Most information to date on prions is derived from studies of scrapie-infected hamsters. Though the precise molecular composition of prions remains elusive, it is established that the protease-resistant scrapie prion protein, PrPSc, is the major, and perhaps the sole, component of the infectious prion particle. PrPSc is derived from a protease-sensitive, host-encoded cellular protein, PrPC, by an as yet undetermined posttranslational modification. That this modification is simply conformational is supported by structural studies using Fourier-transform infrared spectroscopy (FTlR) and circular dichroism which indicate that PrPC is primarily alpha-helical while PrPSc is predominantly beta-sheet. In the proposed studies, attempts will be made to convert purified PrPC into PrPSc by exposing PrPC to perturbations in pH, solvents, detergents and temperature followed by analysis for an increase in its beta-sheet content and the production of PrPSc. Additionally, numerous experimental observations suggest that PrPSc directly interacts with homologous PrPC to produce scrapie prions. Synthetic PrP peptides, which form amyloid as does PrPSc, will be incubated with purified PrPC in an attempt to mimic the presumptive in vivo interaction. Production of PrPSc and prions will be assessed by FTlR, bioassay, electron microscopy and the appearance of protease-resistant proteins on western blots. If conversion of Pro into PrPSc is produced, this would confirm the "protein only" hypothesis of prion structure and replication and immediately provide a system for the evaluation of drugs which might perturb this conversion, thereby ameliorating or preventing disease.